Chronic administration of antidepressants leads to a change in rat brain neurotransmitter receptor binding and function. Since the time necessary for these alterations to occur coincides with reported delay in clinical response to these agents, it has been suggested that these receptor modifications may be related to the mechanism of action of this drug class. In the present application, preliminary data are presented which indicate that changes in the circulating levels of sex hormones modify some of the neurotransmitter receptor responses to antidepressants. This finding may provide a biochemical explanation for the ineffectiveness of these drugs in some patients since affective illness is often associated with changes in the hormonal state of the patient. Using a number of biochemical assays to measure neurotransmitter receptor recognition site number and function, studies are proposed to better define the relationship between hormones and the receptor response to antidepressants, as well as to elucidate themolecular events associated with receptor regulation. Furthermore, data are presented to indicate that co-administration of ACTH with some antidepressants causes a more rapid change in receptor number and function than is observed with the antidepressant alone. Moreover, it has been found that this hormone alone is capable of modifying Beta-adrenergic receptor activity in the brain. These findings suggest that this peptide may play a role in receptor regulation. Studies are described to examine this phenomenon as well. The results of these studies should provide new information about the molecular mechanisms which regulate receptor responses to drugs and thereby yield new insights into the mode of action of antidepressants and possibly into the etiology and treatment of affective illness.